The Connection Among Immunity, Longevity and Nitric Oxide

Jeffrey Bland, Ph.D.

It may seem a stretch to think that our immune function is connected to longevity and to the physiology of nitric oxide, but based upon the most recent scientific discoveries the relationship among them is true. The function of the immune system as we age has been shown to be directly related to our longevity. It has also been shown that interventions that improve immune processes through the upstream modulation of physiological processes that regulate immune system function and aging have direct effects on longevity. There is new information that links nitric oxide as a determinant of human longevity and health span. I was very fortunate to have met and interacted with both Dr. Louis Ignarro and Dr. Ferid Murad in the 1990s, two of the three Nobel Prize winners for their discoveries pertaining to nitric oxide and its effect on the cardiovascular and immune systems. It was these relationships that stimulated my early interest in this important area related to health and longevity over the past thirty years.

Nitric oxide, a simple molecule with the chemical formula NO, plays a critical role in various physiological processes. It is a vasodilator, meaning it helps in the relaxation of blood vessels, improving blood flow and reducing blood pressure. Additionally, NO has been implicated in immune responses, neurotransmission, and cellular metabolism. Nitric oxide is now considered a “master regulator” of many processes associated with biological aging including aging of the immune system.  

The immune system's efficiency declines with age, a phenomenon known as immunosenescence. This decline contributes to increased susceptibility to infections, chronic diseases, and cancer in the elderly. On the flip side, a robust immune system is linked to improved health and longevity. This connection is evident in centenarians, who often exhibit stronger immune systems and nitric oxide dynamics as compared to their less healthy younger counterparts.

 Recent research has highlighted nitric oxide's significant role in both immunity and aging. NO modulates various immune responses. For instance, it is critical in macrophage function – a type of white blood cell that engulfs and digests cellular debris and pathogens. NO is also involved in the regulation of T-cell response, crucial for adaptive immunity.

Nitric Oxide and Immune System Function

In terms of aging, NO has been shown to influence lifespan through various mechanisms. It affects mitochondrial function, oxidative stress, and telomere length – all of which are key factors in the aging process:

1. NO and Mitochondrial Function

Mitochondria, the powerhouses of cells, are vital for energy production. NO interacts with enzymes in mitochondria, affecting their efficiency. Inefficient mitochondria are linked to aging and age-related diseases.

2. Nitric Oxide and Oxidative Stress

Oxidative stress, caused by an imbalance between free radicals and antioxidants in the body, contributes to aging and various diseases. NO can act as a free radical itself, but it also has the capability to neutralize other damaging radicals, thus playing a dual role in oxidative stress.

3. Nitric Oxide and Telomere Length

Telomeres, protective caps at the ends of chromosomes, shorten with each cell division, and their length is an indicator of cellular aging. NO has been implicated in telomere maintenance, potentially influencing the rate at which cells and, by extension, organisms age.

                 4. Nitric Oxide and Immune Function

It has been discovered that nitric oxide can be produced by an enzyme that is called nitric oxide synthase, abbreviated as NOS. This enzyme exists in three forms: endothelial NOS, neuronal NOS and Inducible NOS. Inducible NOS is expressed in the immune system and is a critical player in control of our immune system function.

Production of Nitric Oxide 

Nitric oxide as a master molecular regulator influences these mechanisms determining longevity and health span through modulation of the production of oxygen free radicals such as superoxide anion radical and hydrogen peroxide include nitric oxide (NO) and superoxide anion radical and hydrogen peroxide.  L-arginine, the substrate for nitric oxide synthase (NOS), can restore a healthy ratio between the dangerous superoxide radical and protective nitric oxide to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage. Specific supplements of L-arginine and antioxidants such as vitamin C have been shown to increase nitric oxide production and its bioavailability. Nitric oxide can also be increased through a non-enzymatically controlled process by way of the conversion of dietary nitrate and nitrite into nitric oxide. This occurs to a large extent in the oral cavity due to the presence of specific oral microbiota in a healthy oral microbiome that produce nitrite in the saliva that can then be converted into nitric oxide.   

A number of recent research publications have focused on the role of oral nitrate-reducing bacteria in the oral cavity and the prevention of not only oral infection and cavities, but also the influence on systemic immune function. This has been a major breakthrough in the understanding of both how nitric oxide is produced and its effects as an immune and longevity implicated substance.  

Nitrate that is circulating in the blood is absorbed by the salivary glands and secreted into the oral cavity, where it is reduced to nitrite by the oral nitrate-reducing bacteria. This process was previously considered potentially harmful because nitrate and nitrite can promote the formation of the potentially carcinogenic N-nitrosoamines. However, recent studies have shown that nitrate can also serve as the precursor to nitric oxide and promote nitrite oxide mediated physiological processes the same as if it were produced by the nitric oxide synthase enzymes. These effects are related to immunity, cardiovascular function, and the prevention of cellular senescence.  

The imbalance of nitric oxide in the body is associated with many chronic diseases associated with aging and immune dysregulation. The effects of altered regulation of nitric oxide production have been found to connect to disorders of the gastrointestinal, endocrine, nervous, respiratory, and urogenital systems.  

Diet and Nitric Oxide Production 

Emerging evidence indicates that impaired nitric oxide status plays a key role in cardiometabolic disorders which translates to a reduce life expectancy. Dietary habits play a large role in regulating nitric oxide, and ultra-processed foods have been shown to be associated with lower nitric oxide production.  

Beetroot has been found to contain a high level of nitrate, and beetroot juice has been studied as a dietary precursor for the production of nitric oxide. In recent human clinical trials beetroot juice as a source of dietary nitrate has been found to decrease blood pressure, improve cognitive function and be associated with functional changes associated with longevity. In recent studies of the impact of beetroot juice supplementation on age-related function it was found in older age men to improve muscle speed and power, and in a separate study in post-menopausal women to improve cardiovascular performance and exercise tolerance.

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Conclusion 

There is clear evidence that nitric oxide is a master regulator of physiological function, and its status is dependent on our diet and lifestyle. Foods that are high in proteins that contain higher levels of the amino acid arginine, nitrate, and antioxidants and low in highly processed foods are associated with improved nitric oxide regulation. Regulation of nitric oxide status in turn has a positive impact on immune function and the connection to longevity. Recent studies have indicated that specific nutritional supplements can augment nitric oxide production and contribute to improved immune and cardiometabolic function.  

The triad of immunity, longevity, and nitric oxide presents a complex but fascinating picture of how our bodies fight disease and age. As research progresses, the potential to harness this knowledge to improve human health and lifespan becomes increasingly tangible. It is an exciting time for science, with the promise of groundbreaking discoveries that could redefine our understanding of aging and immunity.

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